Abstract: At present, pathology studies of Parkinson's disease (PD) have shown that the clinical early stage at diagnosis is, in fact, at a pathologically late stage with up to 50-70% of dopaminergic neurons depleted in the substantia nigra. Therefore, there is a critical need for a biomarker capable of detecting pathological changes much earlier. However, when beginning to address this issue, one must first be able to identify a cohort of at-risk preclinical subjects who will eventually develop PD, which is not possible without an early marker. Such a ?chicken-and-egg? problem holds back PD research significantly. This application is conceived based on three well-documented findings: 1) Olfactory dysfunction is prevalent in PD, and central olfactory system is highly affected by PD pathology, approximately 4 years earlier than the substantia nigra; 2) The clinical symptoms are always asymmetric at the diagnosis of H&Y stage-I early onset PD, and as the disease progresses to stage II within a few years, the asymptomatic side of the body inevitably develops motor symptoms; and 3) Postmortem pathological and our recent in vivo MRI studies have demonstrated the asymmetry of pathological status in the two hemispheres at the early stage of disease. Combining these findings and facts creates a unique opportunity to overcome the challenge of identifying preclinical PD subjects, because the asymptomatic hemisphere in stage-I PD offers a sample at a transitional stage between ?preclinical? stage and clinical stage, and early pathology in the central olfactory system offers a site for potential biomarkers for PD. We hypothesize that the clinically asymptomatic hemisphere of stage-I PD is at a transitional stage between ?preclinical? and clinical stage, and there is hemispheric asymmetry in functional deficits in the primary olfactory cortex (POC) of patients at this stage. Using a novel fMRI technique in our preliminary study of stage-I early onset PD, we have found significant asymmetry in odor-related activation deficit at POC. In this application, we propose a prospective cohort study of cognitively-normal stage-I early onset PD patients with olfactory fMRI, morphological MRI of the olfactory bulb (OB) and POC, psychophysical evaluation of smell functions, and clinical assessment of motor deficits. Our goal is to understand the underlying mechanisms of olfactory deficit in PD, and its relationship to disease progression. This goal will be accomplished with the following three specific aims: Specific Aim 1 will test the hypothesis that there is a hemispheric asymmetry in functional deficit in the POC in H&Y stage-I PD; Specific Aim 2 will test the hypothesis that there is a hemispheric asymmetry in morphological change of the OB and POC in H&Y stage-I PD; Specific Aim 3 will test the hypothesis that the functional deficit in the POC and the atrophy of the OB and POC worsen as the disease progresses in the early stages of PD. A successful outcome of this research will provide the necessary foundation for the development of biomarkers for olfactory consequences of PD progression, and also potential surrogate imaging markers for the early detection of PD progression.